Hydrogels are diluted polymer networks that are cross-linked and which contain, by weight, mostly a liquid, but behave like a solid material. The polymers of a hydrogel are hydrophilic, rendering the gel highly absorbent. Hydrogels have important applications in medical devices and implants, as well as in drug delivery vehicles.
There are documents disclosing systems for injectable hydrogels, wherein the injected composition comprises two or more parts which form a gel in situ when mixed.
WO 2010/087912 is directed to a composition comprising a polymer comprising thiol groups and gold nanoparticles which forms a hydrogel. The gel is said to be suitable for anchoring cells and growing cells in a 3-D matrix. The nanoparticles are described as clusters of gold atoms having a size of 0.5 to 250 nm, and the polymer is exemplified as a polysaccharide. Each nanoparticle is said to bind to several thiol groups and thereby act as a multivalent cross-linker. The gelling time for the system disclosed in WO2010/087912 is said to be from 24 to 48 hours.
There are documents that disclose the use of oxidizing substances such as oxygen and hydrogen peroxide to form disulphide crosslinkage from dithiol containing polymers. However, the use of oxygen or hydrogen peroxide in a large amounts brings a risk of explosion and fire, especially during heating. Use of these compounds may also be a hazard to a worker's health. Further, the use of hydrogen peroxide to oxidize two thiol groups may not stop at the formation of a disulphide but may cause further oxidation into a sulfonic acid which might degrade the polymer. Also, the formed acid is toxic both for people coming in contact with the material and the environment.
US 2011/0218298 discloses a method of forming disulphide-crosslinked gels by providing a composition of dithiol polymers and subjecting them to an oxidizing environment containing oxygen, hydrogen peroxide and a tertiary amine, where the amount of oxygen and hydrogen peroxide is low. Even though the inventors state that the reaction was faster, the gelling time was still reported to be around 16 hours. Further, in order to form the gels, organic solvents such as THF had to be used, which would not be suitable for injectable in situ forming gels.
US 2009/026417 discloses a method of forming a gel from thiolated chitosan using an oxidizing agent and/or an external crosslinking agent. The oxidizing agents are said to be hydrogen peroxide, oxygen, horseradish peroxidase or mushroom tyrosinase, and the external crosslinking agent are said to be a low molecular weight aldehyde such as genipin and glutaraldehyde. When using ultra low molecular weight chitosan modified with thiobutylamidine and hydrogen peroxide, a gel reportedly was formed in 5 minutes.
US 2011/0033503 is directed to a spray-on hydrogel of PEG polymers that are cross-linked in situ such that the cross-links are reversible. The PEG is said to be a multi-armed polymer, with for example 4 or 8 arms, having a sulfhydryl, a thiol or a mercaptan moiety, and is cross-linked using hydrogen peroxide or a maleimide or a thiopyridine terminated cross-linker. The gelation time when using the maleimide cross-linker was reported to be almost instant.